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ATAZANAVIR IS A COMPETITIVE INHIBITOR OF SARS-COV-2MPRO, IMPAIRING VARIANTS REPLICATION IN VITRO AND IN VIVO
COVID-19
Reaproveitamento de drogas
Atazanavir
Farmacocinética
Inibidor de protease
Ancoragem molecular
COVID-19
Repurposing drugs
Atazanavir
Protease inhibitor
Pharmacokinetics
Molecular docking
Author
Affilliation
Abstract
Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019
coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of
action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo
assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are
susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that
SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki)
1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content.
ATV was a competitive inhibitor, increasing the Mpro’s Michaelis–Menten (Km) more than sixfold.
Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral
administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice
expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against
lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed
in the lung from infected and treated mice. Our studies may contribute to a better comprehension of
the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this
viral protease.
Keywords in Portuguese
SARS-CoV-2COVID-19
Reaproveitamento de drogas
Atazanavir
Farmacocinética
Inibidor de protease
Ancoragem molecular
Keywords
SARS-CoV-2COVID-19
Repurposing drugs
Atazanavir
Protease inhibitor
Pharmacokinetics
Molecular docking
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